1-p-(omega-aminoalkyl)phenyl-cyclohexanes,cyclohexenes and cyclohexanols

ABSTRACT

1-p-( omega -aminoalkyl)phenyl-substituted and unsubstituted cyclohexanes, cyclohexenes and cyclohexanols, e.g., 2-(4-(1cyclohexen-1-yl)cyclohexyloxy)-N,N,-2-trimethylpropylamine hydrochloride. The compounds are useful as hypolipidemic agents.

nited States Patent Buzzolini 1 July 4, 1972 l-P-(m-AMINOALKYL)PHENYL- OTHER PUBLICATIONS Bencze, Chem. Abs. Vol. 60, pp. 15779- 15780, 1964 [72] Inventor: Mario G. Buzzolini. Morristown. NJ Primary Emmi'fer AleX Maze] 07960 Assistant Examiner-Joseph A. Narcavage Attorney-Gerald D. Sharkin, Frederick H. WeinfeldL Robert [73] Assignee: Sandoz-Wander, Inc., Hanover, N]. Honor Walter Jewell and R'chard VH3 [22] Filed: Aug. 15, 1969 ABSTRACT [21] Appl. No: 850,675 1-p-(w-aminoalkyl)phenyl-substituted and unsubstituted cyclohexanes, cyclohexenes and cyclohexanols, e.g., 2-! 4( I [52] [1.8. CI. ..260/326.5 M, 260/293.82, 260/5707, cyclohexeml yl)cyc|ohexy|oxy] NN 2 trimethy| [51] Int Cl 424/267: 424/ propylamine hydrochloride The compounds are useful as [58] Field of Search ..260/326.5 M, 570.7 [56] References Cited UNITED STATES PATENTS 12 Claims, No Drawings 3,247,199 4/1966 Marxer eta]. ..260/246 This invention relates to l-p-(w-aminoalkyl)phenyl-substituted and unsubstituted cyclohexanes, cyclohexenes and cyclohexanols, intermediates therefor, acid addition salts thereof and process for their preparation.

The compounds of this invention may be represented by the following formula where each of R and R is, independently, hydrogen or lower alkyl of one to four carbon atoms, e.g., methyl, ethyl, propyl or butyl;

each of R is, independently, lower alkyl of one to four carbon atoms, e.g., methyl, ethyl, propyl, or butyl, or both R together form an alkylene bridge of four to five carbon atoms, e.g., both R together with the amino nitrogen form a N-pyrrolidyl substituent,

R is hydrogen or phenyl; and

A is hydrogen;

B is hydrogen or OH; or

A and B together represent a carbon to carbon bond.

The compounds of formula I where A and B are each hydrogen Ia and the other substituents are as defined may be prepared by catalytically hydrogenating the corresponding compounds of formula I where A and B represent a carbon to carbon bond lb.

The catalytic hydrogenation may be carried out over a fairly wide temperature range typically from C. to 100 C., preferably between C. to 80 C. The hydrogenation may be carried out at atmospheric pressure or at superatmospheric pressure, and usually in the range between atmospheric pressure up to 2,000 psi. The hydrogenation is conducted preferably with an approximately required stoichiometric amount of elemental hydrogen and in the presence of inert organic solvent and hydrogenation catalyst of which several are known and available, such as platinum supported on carbon or palladium on carbon. The especially preferred catalyst is palladium supported on carbon, e.g., a catalyst of a minor portion 1 of 3 10 percent palladium on 90 97 percent charcoal. Such charcoal supported palladium catalysts are of a well-known type. The especially preferred solvent for use with palladiumcarbon catalyst is acetic acid. Compounds Ia are conveniently recovered in the form of an acid addition salt, preferably the hydrochloride, and, if desired, may be converted to the free base by conventional procedures, e.g., dissolution of the salt in water and precipitation using a base such as sodium carbonate or sodium hydroxide.

Compounds la may be recovered using conventional techniques such as crystallization.

Compounds lb in acid addition salt form may be prepared from the compounds of formula I where A is hydrogen, and B is OH Ic by dehydration in a known manner such as by contacting compound Ic with a strong acid, preferably a strong inorganic acid such as hydrochloric acid.

Compounds lb may be recovered as the free base by treating the acid addition salt form of compound lb above in water with a base such as sodium hydroxide up to pH 10. The free base of compound lb may, if desired, be reconverted into an acid addition salt form by treating the free base with a strong acid, preferably a strong mineral acid.

Compounds lb may be recovered using conventional techniques such as crystallization.

Compounds Ic may be prepared by reacting a substituted cyclohexanone of the formula with a Grignard compound of the formula wherein R, R R and R have the above stated significance and X is halo of atomic weight of from 35 to 127, followed by conventional hydrolysis.

As illustrated, compounds Ic are produced by the reaction of a compound of formula II with an appropriate Grignard compound of formula III. The reaction is carried out in a conventional manner in the presence of an inert organic solvent and preferably at temperatures between about --1 0 C. to C., followed by hydrolysis in the conventional manner, i.e., in a neutral medium such as water or saturated ammonium chloride solution. Preferred solvents are those customarily employed in Grignard reactions, including, by way of illustration, tetrahydrofuran, dioxane and other ethers such as diethyl ether, more preferably tetrahydrofuran. Compounds Ic may be recovered using conventional recovery techniques such as crystallization.

The compounds II and III employed as starting materials in preparation of compounds 10 are either known or can be prepared from known materials by established procedures. The Grignard compounds of formula III are thus conveniently prepared by reaction of magnesium with the corresponding 4- halo-l-aminoalkoxybenzene and the latter compounds conveniently prepared by reaction of a p-halophenol with the alpha halo derivative of or forming the desired w-aminoalkoxy moiety and having the following formula wherein R, R and X are as defined, and both R, are both hydrogen or lower alkyl but when lower alkyl both R are hydrogen.

It will thus be evident that the reaction of the appropriate phalophenol starting material with a compound IV involves a synthesis of the known Williamson type. The compounds III in which R is lower alkyl are desirably prepared from compound IV in which R, is lower alkyl because such compound IV readily undergo rearrangement on reaction with phenol starting material (phenolate)to form compounds III in which the alpha carbon substituent R is lower alkyl, as described by J .F. Kerswin et al., J.A.C.S. 69, 2961 (1947).

The compounds of formula I and their pharmaceutically acceptable acid addition salts, particularly compound lb, are useful because they possess pharmacological activity in animals. In particular, the compounds are useful as hypolipidemic agents, as evidenced, for example, by having hypocholesteremic activity, as indicated by tests on a group of white rats which are given typically 20 80 milligrams per kilogram of body weight per diem of the compound orally, for 6 days, followed by extraction with isopropanol of serum or plasma after anesthetizing the rats with sodium hexobarbital, and then noting the cholesterol content as compared to that of a control group. The cholesterol content is determined by the Technicon method N 24a. For such usage, the compounds may be administered orally as such or admixed with conventional pharmaceutical carriers. The dosage administered may vary depending on the particular compound employed, the therapy desired and the severity of the condition being treated. In general, satisfactory results are obtained when administered at a daily dosage of from about 1 milligram to about milligrams per kilogram of animal body weight, preferably given in divided doses, 2 to 4 times a day, or in Ingredient Parts by Weight 2-[4-( l-cyclohexen-l-yl)cyclohexyloxy] -N,N,-2-trimethylpropylamine hydrochloride Tragacanth Lactose Corn Starch Talcum Magnesium stearate This invention is illustrated but not limited by the following examples.

EXAMPLE 1 l-[p-( 3-dimethylamino-2-methyl-2-propoxyphenyl) ]cyclohexanol I [3 C H:

CH3 CH3 A solution of 10.0 g. (0.037 mole) of 2-(p-bromophenoxy)- N,N,-2-trimethylpropylamine in 25 ml of tetrahydrofuran is added dropwise to 0.9 g (0.037 mole) of magnesium tumings in 20 ml of tetrahydrofuran. The reaction is carried out under dry nitrogen. After the addition is completed, the resulting mixture is gently refluxed for an additional hour. A solution of 3.43 g (0.035 mole) of cyclohexanone in 30 ml of tetrahydrofuran is then added dropwise at room temperature and the reaction mixture is then kept at reflux temperature for 10 hours and finally hydrolyzed with saturated ammonium chloride solution. The resulting alkaline mixture is extracted twice with diethyl ether, the combined ether layers are washed neutral with water and dried over magnesium sulfate. The drying agent is removed by filtration and the solvent removed by gentle warming under reduced pressure (water pump) to obtain a crude solid. The solid is recrystallized from hexane yielding l-[p-( 3-dimethylamino-2-methyl-2-propoxyphenyl)] cyclohexanol.

EXAMPLE 2 2-[4-( l-cyclohexen-l-yl)cyclohexyloxy]-N,N,-2- trimethylpropylamine hydrochloride H: CH:

C113 CH3 The l-[p-(3-dimethylamino-2-methyl-2-propoxy)] cyclohexanol obtained in Example 1, above, is dissolved in 40 ml of ethanol and treated with an excess of a saturated solution of hydrogen chloride in ethanol and refluxed for 20 minutes. The ethanol is distilled off under reduced pressure leaving a white solid which is triturated several times with diethyl ether. The crude hydrochloride is recrystallized twice from isopropanol yielding 2-[4-( l-cyclohexen-l-yl)cyclohexyloxy]-N,N,-Z-trimethylpropylamine hydrochloride; mp 220.2 222 C. 5

EXAMPLE 3 2-(p-Cyciohexylphenoxy)-N,N,-2-trimethylpropylarnine hydrochloride A solution of 5.0 g. of 2-[4-( l-cyclohexen-l-yl)cyclohexyloxy]-N,N,-Z-trimethylpropylamine hydrochloride of Example 2, in 25 ml. of glacial acetic acid is hydrogenated at atmospheric pressure over 4.8 g. of 10 percent palladium on charcoal. The catalyst is separated by filtration and the solvent evaporated under reduced pressure. The residue is taken up in water, made alkaline with 2N sodium hydroxide and extracted with ether. The ethereal layer is washed neutral with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crude oil is dissolved in 20 ml. of diethyl ether and treated with an excess of a saturated solution of hydrogen chloride in either. The solvent is decanted and the resulting white solid triturated several times with ether. The crude hydrochloride is recrystallized from isopropanol followed by two recrystallizations from acetone percent, isopropanol 5 percent, yielding Z-(p-cyclohexylphenoxy)-N,N,-2-trimethylpropylamine hydrochloride; m.p. 204.5-205.5C.

EXAMPLE 4 l-[p-( 2-Dimethylaminol l -dimethylethoxy)phenyl1-2- phenylcyclohexanol hydrochloride 0H CH3 CH3 -HCl A solution of 10.0 g. (0.037 mole) of 2-(p-bromophenoxy)- N,N,-2-trimethylpropylamine in 25 ml. of tetrahydrofuran is added dropwise to 0.9 g. (0.037 mole) of magnesium turnings in 20 ml. of tetrahydrofuran. The reaction is carried out under dry nitrogen. After the addition is completed, the resulting mixture is gently refluxed for an additional hour. A solution of 6.09 g. (0.035 mole) of 2-phenyl-cyclohexanone in 30 ml. of tetrahydrofuran is then added dropwise at room temperature and the reaction mixture is then kept at reflux temperature for 10 hours and finally hydrolyzed with saturated ammonium chloride solution. The resulting alkaline mixture is extracted twice with diethyl ether, the combined ether layers are washed neutral with water and dried over magnesium sulfate. The drying agent is removed by filtration and the solvent removed by gentle warming under reduced pressure (water pump) to obtain a solid, l-[p-(2-dimethylamino-l,l-dimethylethoxy) phenyl]-2-phenylcyclohexanol hydrochloride.

EXAMPLE 5 N,N-2-Trimethyl-2-[ p-( 6-phenyll -cyclohexenl yl)phenoxy]propylamine hydro-chloride The 1-[p-( Z-dimethylaminol l -dimethylethoxy )phenyl ]-2- phenylcyclo-hexanol hydrochloride obtained in Example 4, above, is dissolved in 40 ml. of ethanol and treated with an ex- EXAMPLE 6 N ,N-Z-Tri methyl-2-[ p-( 2-phenylcyclohexyl) phenoxy]propylamine hydrochloride A solution of 5.0 g. of N,N-2-trimethyl-2]p-(6-phenyl-lcyclohexen-l-yl) phenoxy1propylamine hydrochloride of Example 5, in 25 ml. of glacial acetic acid is hydrogenated at atmospheric pressure over 4.8 g. of percent palladium on charcoal. The catalyst is separated by filtration and the solvent evaporated under reduced pressure. The residue is taken up in water, made alkaline with 2N sodium hydroxide and extracted with ether. The ethereal layer is washed neutral with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crude oil is dissolved in ml. of diethyl ether and treated with an excess of a saturated solution of hydrogen chloride in ether. The solvent is decanted and the resulting white solid triturated several times with ether. The crude hydrochloride is recrystallized from isopropanol followed by two recrystallizations from acetone 95 percent, isopropanol 5 percent, yielding N,N-2-trimethyl- 2-[p-(2-phenylcyclohexyl)]phenoxy propylamine hydrochloride.

EXAMPLE 7 N-[2- p-Cyclohexylphenoxy)ethyl]-pyrrolidine hydrochloride EXAMPLE 8 Ethylamine, N ,N-diethyl-Z-(pcyclohexylphenoxy)hydrochloride Following the procedure of Example 1 and employing equivalent amount, p-bromo-diethylaminoethoxy benzene is reacted with cyclohexanone. The resulting product is treated with an excess of a saturated solution of hydrogen chloride following the procedure of Example 2. The resulting product ethylamine, N,N-diethyl-2-(p-cyclohexenylphenyl)hydrochloride, m.p. l64-166C. is then hydrogenated following the procedure of Example 3 to obtain upon crystallization the product ethylamine, N,N-diethyl-2-(p cyclohexylphenoxy)hydrochloride; m.p. l-1 87C.

What is claimed is:

1. A compound of the formula R2 1'! R R B 1 30 I R R,

where each of R and R is, independently, hydrogen or lower alkyl of one to four carbon atoms,

each of R is, independently, lower alkyl of one to four carbon atoms, or both R together form an alkylene bridge of four to five carbon atoms, R is hydrogen or phenyl, and A is hydrogen, B is hydrogen or OH; or I A and B together represent a carbon to carbon bond, or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1 which is l-[p-(3- dimethylamino-2-methyl-Z-propoxyphenyl) ]cyclohexanol.

3. The compound of claim 1 which is 2-[4-( l cyclohexenl yl) cyclohexyloxy]-N,N-2-trimethylpropylamine hydrochloride.

4. The compound of claim 1 which is 2-(p-cyclohexylphenoxy )-N,N,-2-trimethylpropylamine hydrochloride.

5. The compound of claim 1 which is 1-[p-(2- dimethylamino-l,1-dirnethylethoxy)phenyl]-2-phenylcyclohexanol hydrochloride.

6. The compound of claim 1 which is N,N-2-trimethyl-2-[p- (6-phenyll-cyclohexenl-yl )phenoxy1propylamine hydrochloride.

7. The compound of claim 1 which is N,N-2-trirnethyl-2-[p- 2-phenylcyclohexyl)phenoxy]propylamine hydrochloride.

8. The compound of claim 1 which is N-[2-(p-cyclohexylphenoxy) ethyl]-pyrrolidine hydrochloride.

9. The compound of claim 1 which is ethylamine, N,N- diethyl-2-(p-cyclohexylphenoxy)hydrochloride.

10. The compound of claim 1 which is ethylamine, N,N- diethyl-2-(p-cyclohexenylphenyl)hydrochloride.

11 A compound of the formula:

where each of R and R is, independently, hydrogen or lower alkyl of one to four carbon atoms,

each of R, is, independently, lower alkyl of one to four carbon atoms, or both R together form an alkylene bridge of four carbon atoms, R, is hydrogen or phenyl, and A and B together represent a carbon to carbon bond, or A is hydrogen and B is OH, or a pharmaceutically acceptable acid addition salt thereof. 12 A compound according to claim 1 wherein R is hydrogen. 

2. The compound of claim 1 which is 1-(p-(3-dimethylamino-2-methyl-2-propoxyphenyl))cyclohexanol.
 3. The compound of claim 1 which is 2-(4-(1-cyclohexen-1-yl) cyclohexyloxy)-N,N-2-trimethylpropylamine hydrochloride.
 4. The compound of claim 1 which is 2-(p-cyclohexylphenoxy)-N,N, -2-trimethylpropylamine hydrochloride.
 5. The compound of claim 1 which is 1-(p-(2-dimethylamino-1,1-dimethylethoxy)phenyl)-2-phenylcyclohexanol hydrochloride.
 6. The compound of claim 1 which is N,N-2-trimethyl-2-(p-(6-phenyl-1-cyclohexen-1-yl)phenoxy)propylamine hydrochloride.
 7. The compound of claim 1 which is N,N-2-trimethyl-2-(p-(2-phenylcyclohexyl)phenoxy)propylamine hydrochloride.
 8. The compound of claim 1 which is N-(2-(p-cyclohexylphenoxy) ethyl)-pyrrolidine hydrochloride.
 9. The compound of claim 1 which is ethylamine, N,N-diethyl-2-(p-cyclohexylphenoxy)hydrochloride.
 10. The compound of claim 1 which is ethylamine, N,N-diethyl-2-(p-cyclohexenylphenyl)hydrochloride. 11 - A compound of the formula: 